After $100 billion and questionable approval processes, it may be time to look at other theories of Alzheimer’s causation.
Another anti-amyloid biologic has failed to beat placebo in a long-running trial, leaving some experts wondering about the future of amyloid as a treatment pathway for Alzheimer’s disease.
Earlier this month preliminary findings from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (“A4 Study“) of solanezumab were released showing no statistical difference between the Eli Lilly biologic and placebo groups in their Preclinical Alzheimer Cognitive Composite scores. The 1150 eligible participants, including some Australians, ranged from 65 to 85 years, and had normal thinking and memory ability but evidence of elevated amyloid plaque accumulation at baseline.
Professor Colin Masters, head of the neuropathology and neurodegeneration laboratory at the Florey Institute, and coordinator of the Australian arm of the A4 study, is one of the pioneers of the amyloid hypothesis. He remained bullish despite the disappointment of the A4 study results.
“Many people are extremely disappointed by the solanezumab results, for sure,” Professor Masters said. “Some of [the participants] have been with us for nearly eight years. Of course, we were hoping for a positive result – but that’s the nature of these clinical trials. Some things work, some things only work a little bit, and some things don’t work at all.”
Professor Masters said he was hopeful that many of the A4 participants would now be eligible for a new trial, AHEAD. This will follow the same trial protocol to test another monoclonal antibody, lecanemab, developed by Eisai, which developed aducanumab with Biogen.
“Lecanemab is looking very good at this point in people with moderate or very early-stage Alzheimer’s,” Professor Masters said. “But we think it will work even better in people who are in the preclinical stages [like the participants in the A4 study].
“The Veterans Health Administration in the US has already decided to pay for it. That’s a big step. They have recognised the value of lecanemab.”
The question of the effectiveness of lecanemab and the only other anti-amyloid to receive FDA approval – aducanumab – is up for debate, however.
Aducanumab and lecanemab were fast-tracked by the FDA based on their ability to remove amyloid from the brain, not for any improvement in clinical signs of Alzheimer’s disease, under its Accelerated Approvals scheme in which only a surrogate endpoint has to be met.
That’s problematic, according to Professor Bryce Vissel, from UNSW Sydney, director of the Centre for Neuroscience and Regenerative Medicine at St Vincent’s Hospital Sydney.
“I believe that both those drugs were fast tracked through the FDA on the basis of understanding this is a desperate disease,” Professor Vissel said.
“We all understand a treatment is needed. None of us are in any way wanting anything else other than a cure.
“[But] the way aducanumab was approved was concerning. The subsequent congressional inquiry profoundly reprimanded both the FDA and [sponsor] Biogen for the way they went about the approval of aducanumab. It was approved on the basis of its ability to remove amyloid, not on the basis of its ability to improve cognition.
“In the case of aducanumab there have been two clinical trials. One showed, on post hoc analysis – meaning they went back and relooked at the data – evidence of cognitive improvement in the patients treated. The other trial showed no benefit at all.
“It therefore cannot be stated at this time that aducanumab does anything to improve cognition. The data does not support that statement,” said Professor Vissel.
“Lecanemab on the other hand did in a subsequent phase III trial show some small effect on cognition, though there is debate as to whether this is a meaningful benefit, and I believe more research on benefit-risk assessment might be needed before it is used clinically in the AD dementia population, which has so many comorbidities which might influence the benefit risk assessment.
“In the end though, both drugs were essentially approved on the basis of the amyloid hypothesis, which is in fact still a hypothesis. There are two parts to the amyloid hypothesis. One part explains how amyloid is generated, and we’ve learned a lot about that through some absolutely brilliant science. And we now know how to remove it from the brain.
“But the part of the theory that has not been proven is whether amyloid is the toxic agent that kills neurons. It’s never been shown in any human, ever.”
Part of the problem, says Professor Vissel, is the definition of Alzheimer’s disease, which includes amyloid.
“You define Alzheimer’s disease by the presence of amyloid. But my point is that the jury is still out as to whether amyloid is a driver of a disease rather than a marker of the disease.
“Even if it’s a marker of disease, most scientists would agree that amyloid likely has some role. Whether that role is minor, or significant, is the point in contention,” he said.
“It was an incredibly compelling case for many years that amyloid was a driver of the disease … it was a time of extraordinary excitement at the time that the amyloid hypothesis was conceived. There’s been a massive investment as a result – in excess of $US100 billion has been spent on the amyloid approach.
“They’re going to continue to push it because some people are very ensconced in this hypothesis. And the more they do push forward with treatment efforts based on amyloid, the more we will learn, including whether the amyloid has any role.
“But I think that a number of us who are not associated with the amyloid world, and who aren’t advocates for it, would be saying that we’ve got to start looking elsewhere and come up with a different theory. That theory would still have to account for the amyloid observed in the brain but may not be solely dependent on it as a cause of dementia.”
Some alternative hypotheses could include possible roles for inflammation, or infection.
“More realistically, if you’re talking about Alzheimer’s dementia, it may turn out that it may be more than one type of disease,” said Professor Vissel.
“Maybe you end up calling it Alzheimer’s disease, but it might be Alzheimer’s disease type 1, 2, 3 etc. They’ve all got amyloid in the brain, but actually the etiological cause of their dementia may be something different in terms of their life history, in terms of their genetics, or a combination of those things.
“There are so many other pathologies in the brain of people with Alzheimer’s, and that includes Tau tangles, microgliosis, blood vessel disease – there are a lot of pathologies.
“The extent to which these other pathologies are also markers or etiologically important, we just don’t know.
“Infection may be very important in causing Alzheimer’s long-term chronic effects. Herpes simplex virus has been strongly implicated. We know HIV increases risk of dementia. And so on. There are certain bacteria that are associated with increased risks of Alzheimer’s. We don’t know if those bacteria are infecting the brain, or whether they’re creating a pro-inflammatory environment.”
Meanwhile, Brodtmann et al, writing in the Medical Journal of Australia, said even though aducanumab and lecanemab were not yet approved here, the medical community needed to ready themselves and the dementia community.
“At present, patients receiving any Alzheimer disease monoclonal antibody therapy require an Alzheimer disease diagnosis validation by amyloid PET or cerebrospinal fluid (CSF) Alzheimer disease biomarker testing — neither of which are available on universal health care in Australia and New Zealand,” they wrote.
“The socioeconomic implications of any potential approved therapy are a major consideration.”
Other problems include the need for rapid access to cognitive clinicians, neuropsychologists, neuroradiologists, advanced neuroimaging, and cerebrospinal fluid and blood biomarker capabilities; APOE allele tests are not reimbursed in Australia and New Zealand, with some patients also concerned about the consequences of genetic testing for health or life insurance; and conservative estimates of demand for an intravenous Alzheimer disease treatment would represent a fivefold increase in patients compared with multiple sclerosis.
“Therapeutic advancement is well underway, and the medical community needs to keep pace,” Brodtmann et al concluded.
Biogen withdrew its application for TGA aducanumab approval in June last year.
A spokeswoman for Biogen told TMR: “The decision to withdraw the submission followed interactions with the TGA indicating that the data provided so far would not be sufficient to support a positive recommendation on the registration of this medicine.
“Further clinical trials are currently being undertaken with aducanumab before a decision will be made on whether a further submission will be made to the TGA.
“Biogen stands by the safety and efficacy of aducanumab and looks forward to upcoming data readouts to continue to provide important information on the science of this new class of compound.”
A spokesman for Eisai said the company was in the “early stages” of seeking registration for lecanemab.
“I can confirm that we have commenced consultation with the TGA and have plans to make lecanemab available … at the earliest possible time,” he said.
